Project Summary In the previous U19 award, we developed a non-genotoxic antibody based method of conditioning animal recipients for hematopoietic stem/progenitor cell (HSPC) transplantation. This approach is now being developed for human use and non-human primate testing by Magenta Therapeutics, the commercial participant in this proposal. We also developed a method of enhancing T cell neogenesis post-transplantation that takes advantage of prior work defining the bone marrow niche for T-competent progenitors, creating an easy to administer, off the shelf bone marrow cryogel. Subcutaneous injection of the cryogel leads to improved T competent common lymphoid progenitor (CLP) production, increased thymocytes, TREC+ cells, mature T cells, expanded TCR repertoire and improved immune function in mouse models. Here, we will combine it with the gene modification technology of the Cannon and Kiem labs and the antibody-drug conjugate technology of Magenta to determine whether we can increase the regeneration of a functionally complex, HIV protected adaptive immune system to protect against acute HIV infection, control viremia in infected hosts and potentially, reduce the tissue reservoir of infected cells. The strengths of the Scadden lab in hematopoiesis and transplant and the Allen lab in HIV infection and immunity will complement each other in testing this approach in humanized mice. We will closely interact with the Cannnon and Kiem labs on gene modifying approaches to engineer anti-HIV HSPC and extend testing to the non-human primate. Collectively, these efforts will provide immediate pre-clinical testing a of a strategy to cure HIV through low-toxicity approaches to rebuild an infected individual?s immune system.